Extracellular Vesicle-Mediated Metastasis Suppressors NME1 and NME2 Modify Lipid Metabolism in Fibroblasts
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA870897 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21121324_1.fastq.gz | Fastqsanger.gz | |||
| SRR21121324_2.fastq.gz | Fastqsanger.gz | |||
| SRR21121325_1.fastq.gz | Fastqsanger.gz | |||
| SRR21121325_2.fastq.gz | Fastqsanger.gz | |||
| SRR21121326_1.fastq.gz | Fastqsanger.gz |
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Project description:Our aim was to understand how vesicular NME1 and NME2 released by breast cancer cells influence the tumour microenvironment. As a model, we used human invasive breast carcinoma cells overexpressing NME1 or NME2, and first analysed in detail the presence of both isoforms in EV subtypes by capillaryWestern immunoassay (WES) and immunoelectron microscopy. Data obtained by both methods showed that NME1 was present in medium-sized EVs or microvesicles, whereas NME2 was abundant in both microvesicles and small-sized EVs or exosomes. Next, human skin-derived fibroblasts were treated with NME1 or NME2 containing EVs, and subsequently mRNA expression changes in fibroblasts were examined. RNAseq results showed that the expression of fatty acid and cholesterol metabolism-related genes was decreased significantly in response to NME1 or NME2 containing EV treatment. We found that FASN (fatty acid synthase) and ACSS2 (acyl-coenzyme A synthetase short-chain family member 2), related to fatty acid synthesis and oxidation, were underexpressed in NME1/2-EV-treated fibroblasts. Our data show an emerging link between NME-containing EVs and regulation of tumour metabolism.
2022-08-21 | GSE211556 | GEO
Project description:Simple Summary Communication between cancer and stromal cells involves paracrine signalling mediated by extracellular vesicles (EVs). EVs transmit essential factors among cells of the tumour microenvironment. EVs derived from both cancer and stromal cells have been implicated in tumour progression. In this study, we focused on the first identified metastasis suppressor NME1, and on its close homolog NME2, and investigated their function in EVs in the interplay between cancer and stromal cells. Abstract Nowadays, extracellular vesicles (EVs) raise a great interest as they are implicated in intercellular communication between cancer and stromal cells. Our aim was to understand how vesicular NME1 and NME2 released by breast cancer cells influence the tumour microenvironment. As a model, we used human invasive breast carcinoma cells overexpressing NME1 or NME2, and first analysed in detail the presence of both isoforms in EV subtypes by capillary Western immunoassay (WES) and immunoelectron microscopy. Data obtained by both methods showed that NME1 was present in medium-sized EVs or microvesicles, whereas NME2 was abundant in both microvesicles and small-sized EVs or exosomes. Next, human skin-derived fibroblasts were treated with NME1 or NME2 containing EVs, and subsequently mRNA expression changes in fibroblasts were examined. RNAseq results showed that the expression of fatty acid and cholesterol metabolism-related genes was decreased significantly in response to NME1 or NME2 containing EV treatment. We found that FASN (fatty acid synthase) and ACSS2 (acyl-coenzyme A synthetase short-chain family member 2), related to fatty acid synthesis and oxidation, were underexpressed in NME1/2-EV-treated fibroblasts. Our data show an emerging link between NME-containing EVs and regulation of tumour metabolism.
| S-EPMC9406105 | biostudies-literature
Project description:Protein phosphorylation by kinases regulates mammalian cell functions, such as growth, division, and signal transduction. Among human kinases, NME1 and NME2 are associated with metastatic tumor suppression, but remain understudied due to the lack of tools to monitor their cellular substrates. In particular, NME1 and NME2 are multi-specificity kinases phosphorylating serine, threonine, histidine, and aspartic acid residues of substrates, and the heat and acid sensitivity of phosphohistidine and phosphoaspartate complicates substrate discovery and validation. To provide new substrate monitoring tools, we established the γ-phosphate modified ATP analog, ATP-biotin, as a cosubstrate for phosphorylbiotinylation of NME1 and NME2 cellular substrates. Building upon this ATP-biotin compatibility, the Kinase-catalyzed Biotinylation with Inactivated Lysates for Discovery of Substrates (K-BILDS) method enabled validation of a known substrate and the discovery of seven NME1 and three NME2 substrates. Given the paucity of methods to study kinase substrates, ATP-biotin and the K-BILDS method are valuable tools to characterize the roles of NME1 and NME2 in human cell biology.
2024-10-17 | PXD051411 | Pride
Project description:Fatty acid homeostasis is critical for normal cellular physiology and leads to severe diseases when deregulated. Here we report Nucleoside-Diphosphate Kinase 1 and 2 (NME1/2) as major cellular co-enzyme A (CoA) and acetyl-CoA binding proteins and negative regulators of de novo lipogenesis (DNL). Structural studies demonstrate that Nme1 recognizes CoA through its nucleotide moiety, which competes for binding with ADP/ATP. By using a Nme2 ko mouse model, we observe that NME2 is required for the gene transcriptional response to a high fat diet (HFD) in liver cells, leading to a repression of lipogenesis and the activation of a protective gene response. Nme2 ko mice submitted to a HFD challenge are unable to repress key lipogenic genes, resulting in an excessive triglyceride synthesis and liver steatosis. Mechanistically, the NME2-dependent down-regulation of DNL in response to HFD changes the balance for the use of acetyl-CoA between the competing paths of acetylation and DNL, thereby increasing TSS-targeted histone acetylation and gene activation. A structure-guided generation of a NME1 mutant, with intact NDK activity, but unable to bind CoA, directly demonstrates the functional impact of acetyl-CoA/CoA binding by NME1/2 in repressing DNL. Taken together, these findings highlight a yet unknow protective liver response to HFD, regulated by multi-ligand binding proteins which act as direct sensors for the cellular levels of NDP/NTP and CoA/acetyl-CoA.
2023-08-01 | GSE198687 | GEO
Project description:Fatty acid homeostasis is critical for normal cellular physiology and leads to severe diseases when deregulated. Here we report Nucleoside-Diphosphate Kinase 1 and 2 (NME1/2) as major cellular co-enzyme A (CoA) and acetyl-CoA binding proteins and negative regulators of de novo lipogenesis (DNL). Structural studies demonstrate that Nme1 recognizes CoA through its nucleotide moiety, which competes for binding with ADP/ATP. By using a Nme2 ko mouse model, we observe that NME2 is required for the gene transcriptional response to a high fat diet (HFD) in liver cells, leading to a repression of lipogenesis and the activation of a protective gene response. Nme2 ko mice submitted to a HFD challenge are unable to repress key lipogenic genes, resulting in an excessive triglyceride synthesis and liver steatosis. Mechanistically, the NME2-dependent down-regulation of DNL in response to HFD changes the balance for the use of acetyl-CoA between the competing paths of acetylation and DNL, thereby increasing TSS-targeted histone acetylation and gene activation. A structure-guided generation of a NME1 mutant, with intact NDK activity, but unable to bind CoA, directly demonstrates the functional impact of acetyl-CoA/CoA binding by NME1/2 in repressing DNL. Taken together, these findings highlight a yet unknow protective liver response to HFD, regulated by multi-ligand binding proteins which act as direct sensors for the cellular levels of NDP/NTP and CoA/acetyl-CoA.
2023-08-01 | GSE198686 | GEO
Project description:Non-metastatic 2 (NME2) is one of the first discovered suppressors of metastases. However, the molecular mechanisms underlying its anti-metatsic activity remain insufficiently characterized. We hypothesized that large scale transcriptional potential of NME2 might be at the core of this function. Using a combination of gene expression meta-analysis, and high throughput genomic assays, we explored the transcriptional targets of NME2. Specifically, we found >250 binding sites of NME2 across human gene promoters. Several of the novel targets identified in this way regulated cell adhesion and survival. We subsequently constructed NME2 target gene network which delineated a transcriptional program responsive to NME2 capable of restricting metastasis.
2011-02-08 | GSE18284 | GEO
Project description:Non-metastatic 2 (NME2) is one of the first discovered suppressors of metastases. However, the molecular mechanisms underlying its anti-metatsic activity remain insufficiently characterized. We hypothesized that large scale transcriptional potential of NME2 might be at the core of this function. Using a combination of gene expression meta-analysis, and high throughput genomic assays, we explored the transcriptional targets of NME2. Specifically, we found >250 binding sites of NME2 across human gene promoters. Several of the novel targets identified in this way regulated cell adhesion and survival. We subsequently constructed NME2 target gene network which delineated a transcriptional program responsive to NME2 capable of restricting metastasis. Three sets of ChIP vs. mock-ChIP experiments were done. pcDNA plasmid was transfected to lung cancer, A549 cells to express NME2 tagged with MYC epitope which was subsequently immunoprecipitated using anti-MYC antibodies (after 48 hours of transfection). Non-specific IgG was used for mock immunoprecipitation.
2011-02-08 | E-GEOD-18284 | biostudies-arrayexpress
Project description:Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. On a single MSG basis, genes have been identified with expression patterns inverse to a MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of many MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. We used microarrays to evaluate the modification in gene expression profile after donregulation of multiple metastasis suppressors (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1) in the breast cancer cell line, MCF7. MCF7 cell line was transfected with siRNA targeting each of 19 metastasis suppressors (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1). Two siRNA sequences (siRNA1 and siRNA2) were used for each metastasis suppressor. Two time points (48hr and 96hr) were considered as end of transfection in order to measure early and late effects of the metastasis suppressors downregulation.
2013-12-27 | E-GEOD-53668 | biostudies-arrayexpress
Project description:Purpose: Herein we demonstrate that UV-induced melanomas of low metastatic potential in mice that overexpress HGF and harbor deletion of the Ink4a/p16 locus (HP strain) are converted to highly metastatic forms by virtue of hemizygous deletion of the metastasis suppressor genes Nme1 and Nme2 (HPN strain). The striking difference in metastatic activity between HP and HPN melanomas strains provided a powerful system for identifying molecular profiles associated with metastatic activity. Methods: Primary and metastatic melanoma RNAseq profiling. Results: RNA-seq analysis of primary melanomas identified a 32-gene expression signature that was strongly associated with the HPN genotype and lung metastatic activity (HPN lung metastasis signature, or HPN-LMS). Expression of the HPN-LMS was highly predictive of overall survival in human cohorts of cutaneous melanoma (SKCM) and uveal melanoma (UVM) patients of The Cancer Genome Atlas (TCGA). Conclusions: Three HPN-LMS genes (ARRDC3, NYNRIN, RND3) associated with longer survival in SKCM and/or UVM patients exhibited strong anti-invasion activity in human melanoma cells, consistent with roles as effectors of the metastasis suppressor functions of Nme1 and Nme2. The HP/HPN mouse paradigm has thus yielded a network of potential therapeutic targets and prognostic markers for clinical management of metastatic melanoma.
2021-08-02 | GSE181207 | GEO